Zinc Oxide-Catalyzed Dehydrogenation of Primary Alcohols into Carboxylic Acids

Article abstract of DOI:10.1002/chem.201804402

Zinc oxide has been developed as a catalyst for the dehydrogenation of primary alcohols into carboxylic acids and hydrogen gas. The reaction is performed in mesitylene solution in the presence of potassium hydroxide, followed by workup with hydrochloric acid. The transformation can be applied to both benzylic and aliphatic primary alcohols and the catalytically active species was shown to be a homogeneous compound by a hot filtration test. Dialkylzinc and strongly basic zinc salts also catalyze the dehydrogenation with similar results. The mechanism is believed to involve the formation of a zinc alkoxide which degrades into the aldehyde and a zinc hydride. The latter reacts with the alcohol to form hydrogen gas and regenerate the zinc alkoxide. The degradation of a zinc alkoxide into the aldehyde upon heating was confirmed experimentally. The aldehyde can then undergo a Cannizzaro reaction or a Tishchenko reaction, which in the presence of hydroxide leads to the carboxylic acid.

Full text of DOI:10.1002/chem.201804402

A Journal of
Accepted Article
Title: Zinc Oxide-Catalyzed Dehydrogenation of Primary Alcohols into
Carboxylic Acids
Authors: Fabrizio Monda and Robert Madsen
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Zinc Oxide-Catalyzed Dehydrogenation of Primary Alcohols into
Carboxylic Acids
Fabrizio Monda and Robert Madsen*[a]
Abstract: Zinc oxide has been developed as a catalyst for the
dehydrogenation of primary alcohols into carboxylic acids and
hydrogen gas. The reaction is performed in mesitylene solution in
the presence of potassium hydroxide followed by workup with
hydrochloric acid. The transformation can be applied to both benzylic
and aliphatic primary alcohols and the catalytically active species
was shown to be a homogeneous compound by a hot filtration test.
Dialkylzinc and strongly basic zinc salts also catalyze the
dehydrogenation with similar results. The mechanism is believed to
involve the formation of a zinc alkoxide which degrades into the
aldehyde and a zinc hydride. The latter reacts with the alcohol to
form hydrogen gas and regenerating the zinc alkoxide. The
degradation of a zinc alkoxide into the aldehyde upon heating was
formation of zinc(II) hydrides[7] which are known to be able to
reduce C=O and C=N bonds.
A few dehydrogenations with the release of hydrogen gas
have also been described with zinc(II) catalysts. Zinc triflate
catalyzes the borylation and silylation of terminal alkynes with
boranes and silanes,[8] respectively, as well as the N-silylation of
indoles with silanes.[9] Zinc oxide catalyzes the dehydrogenation
of alcohols in the gas phase at temperatures around 400 °C and
the reaction is often accompanied by a competing dehydration
reaction.[10] In addition, heating a mixture of a primary alcohol, a
zinc salt and sodium hydroxide to 210 – 260 °C under neat
conditions has been reported to afford
a mixture of the
corresponding ester and carboxylic acid in moderate yields.[11]
The transformation is believed to proceed through a Tishchenko
reaction[12] of the intermediate aldehyde to give the ester. Thus,
it appears that zinc(II) species are able to mediate the necessary
molecular pathways for releasing hydrogen gas and it is
therefore conceivable that they will also catalyze alcohol
dehydrogenations at more moderate temperatures in solution.
Herein, we describe the development of a zinc(II)-catalyzed
protocol for the dehydrogenation of primary alcohols into
carboxylic acids. Zinc oxide was shown to be the preferred
catalyst and with a price of only $1/kg it constitutes by far the
most inexpensive catalyst for alcohol dehydrogenation in
solution.[1-3] The acceptorless dehydrogenative synthesis of
carboxylic acids from alcohols has previously been described
with a 0.1 – 5% loading of ruthenium,[13] iridium,[14] palladium,[15]
rhodium,[16] silver[17] and nickel[18] catalysts at reflux temperature
in water, toluene or mesitylene solution. The dehydrogenative
protocol constitutes a benign alternative to alcohol oxidation to
carboxylic acid which is usually performed with a stoichiometric
metal oxide or by a catalytic procedure with a stoichiometric co-
oxidant.[19]
confirmed experimentally. The aldehyde can then undergo
a
Cannizzaro reaction or a Tishchenko reaction which in the presence
of hydroxide leads to the carboxylic acid.
Introduction
The acceptorless dehydrogenation of alcohols has gained much
attention for the synthesis of imines, esters, amides, carboxylic
acids, heterocycles and aldol products.[1] The reactions only
produce hydrogen gas as a co-product and does not require any
stoichiometric oxidants. The most widely used catalysts have
been complexes based on the platinum group metals such as
ruthenium and iridium.[1] More recently, different iron, cobalt and
manganese complexes have also been shown to catalyze the
dehydrogenations.[2] In addition, nickel, copper and molybdenum
catalysts have been employed in several special cases.[3] Zinc,
however, has gained very little interest for catalyzing the
acceptorless dehydrogenation of alcohols.
Due to its poor redox properties zinc catalysis is often
viewed as being limited to Lewis acid mediated reactions. Zinc
exists in oxidation states 0 and +2 and only in the latter is it
possible to form complexes with ligands. However, in recent
years an increasing number of zinc(II)-catalyzed oxidations with
hydroperoxides and reductions with hydride sources have been
developed.[4] The last category includes hydrosilylation of
ketones, esters, imides and amides with silanes[5] as well as
hydrogenation of ketones and imines with hydrogen gas.[6] Most
of the transformations are believed to proceed through the
Results and Discussion
The transformation was discovered while attempting to use zinc
metal as a reducing agent for other Earth-abundant metals in the
presence of water and hydroxide. We have previously performed
a dehydrogenative self-condensation of 1-phenylethanol into 3-
methyl-1,3-diphenylpropan-1-one with a ruthenium catalyst.[20]
The reaction is carried out at reflux temperature with one equiv.
of potassium hydroxide. Several inexpensive metals[2] were
investigated as new catalysts for this transformation with
different ligands and zinc metal as a reducing agent. However, it
was quickly realized that zinc was responsible for the conversion
into the product. In fact, reacting the alcohol with 0.25 equiv. of
Zn in mesitylene solution gave 45% yield of the ketone product
with some unreacted alcohol remaining (Scheme 1). Zinc metal
is known to react with water in organic solvents and produce
[a]
F. Monda, Prof. Dr. R. Madsen
Department of Chemistry
Technical University of Denmark
2800 Kgs. Lyngby (Denmark)
E-mail: rm@kemi.dtu.dk
Supporting information for this article is given via a link at the end of
the document.
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zinc oxide upon heating.[21] Therefore, we speculated that the
actual catalyst was zinc oxide which was confirmed by repeating
the reaction with this salt to give the ketone in 49% yield. Again,
unreacted alcohol was responsible for the moderate yield and it
was not possible to further optimize the reaction. Instead, it was
decided to investigate the transformation with a primary alcohol
which would presumably be more reactive.
essentially the same yield was obtained with 20% of Zn(OMe)2
(entry 15). Control experiments revealed that zinc oxide and
potassium hydroxide were both vital for the transformation
(entries 16 and 17). Thus, an optimized protocol has been
developed for the acceptorless dehydrogenation of alcohols into
carboxylic acids by using zinc oxide and potassium hydroxide in
refluxing mesitylene (entry 14).
Table 1. Optimization of zinc-catalyzed dehydrogenation.[a]
Scheme 1. ZnO-catalyzed self-condensation of 1-phenylethanol.
Entry
[Zn]
Conversion [%][b]
Yield [%][c]
1
ZnO
78
62
0
58
58
0
Indeed, reacting benzyl alcohol with 10% of zinc oxide and
one equiv. of potassium hydroxide in refluxing mesitylene now
furnished the carboxylic acid in 58% isolated yield after workup
by acidification (Table 1, entry 1). However, full conversion of
the alcohol was still not obtained and a number of experiments
were therefore performed to improve the transformation.
Replacing zinc oxide with zinc metal gave a very similar
outcome (entry 2) while poor results were obtained with lithium
hydroxide and sodium hydroxide as the base (entries 3 and 4).
Additives also gave a lower yield (entries 5 and 6) while the
reaction with p-cymene as the solvent furnished the acid in 73%
yield (entry 7). The improved yield in the latter case is most likely
due to the higher reaction temperature since no conversion of
the alcohol was obtained upon refluxing the reactants in toluene
or diglyme. As a result, it was decided to continue the
optimization in mesitylene solution.
2
Zn
3[d]
4[e]
5[f]
ZnO
ZnO
62
40
47
99
91
86
76
97
14
89
99
99
18
0
18
32
27
73
54
56
51
62
0
ZnO
6[g]
7[h]
8
ZnO
ZnO
Et2Zn
Me2Zn
Zn(HMDS)2
Zn(OMe)2
ZnO[i]
ZnO
9
10
11
Several other zinc sources were also investigated and
interestingly Et2Zn, Me2Zn, Zn(HMDS)2 and Zn(OMe)2 all gave
yields similar to zinc oxide and with a slightly higher alcohol
conversion (entries 8–11). This indicates that the catalytically
active species is the same in all cases regardless of the zinc
source. Therefore, the optimization continued with the
inexpensive zinc oxide catalyst. The morphology of this oxide
had no influence on the outcome, but when a zinc oxide
dispersion in water was employed, the reaction stalled (entry 12).
This could suggest that water had a detrimental influence on the
dehydrogenation and explain the cumbersome reaction in
Scheme 1 where water is formed as a byproduct. In fact,
commercial samples of potassium hydroxide contains 0.35 –
0.55 equiv. of water per equiv. of hydroxide and a new protocol
was therefore devised to decrease the amount of water in the
reaction. First, potassium hydroxide was mixed with zinc oxide
and the mixture heated to 170 °C under vacuum for 1 h. This
produced a molten slurry to which benzyl alcohol and mesitylene
were added. After stirring the mixture at reflux for 18 h the acid
was now isolated in 72% yield with an improved conversion of
the alcohol (entry 13). To ensure complete conversion of benzyl
alcohol, the amounts of zinc oxide and potassium hydroxide
were increased to 20% and 2 equiv., respectively, which now
afforded 91% yield of benzoic acid (entry 14). Notably,
12
13[j]
14[j,k,l]
15[j,k,l]
16[l]
17[k,m]
72
91
90
0
ZnO
Zn(OMe)2
-
ZnO
0
[a] Reaction conditions: Benzyl alcohol (2 mmol), [Zn] (0.2 mmol), KOH (2
mmol), mesitylene (3 mL), reflux, 18 h. [b] Determined by GC. [c] Isolated
yield. [d] With LiOH instead of KOH. [e] With NaOH instead of KOH. [f] With
1 equiv. of LiCl as additive. [g] With 1 equiv. of KF as additive. [h] In p-
cymene at 177 °C. [i] 20 wt.% dispersion in water. [j] [Zn] and KOH premixed
at 170 °C for 1 h. [k] With 20% of [Zn]. [l] With 2. equiv. of KOH. [m] Without
KOH.
The procedure was now applied to a variety of primary
alcohols to explore the substrate scope and limitations of the
reaction. First, several other benzylic alcohols were subjected to
the dehydrogenation (Table 2). p-Methylbenzyl alcohol afforded
p-toluic acid in 85% isolated yield (entry 1) while the p-methoxy
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analogue gave p-anisic acid in 79% yield (entry 2). Almost the
same outcome was obtained with p-methylthiobenzyl alcohol
9
70
illustrating the compatibility of
a
thio ether with the
transformation (entry 3). p-Phenyl- and p-benzyloxybenzyl
alcohol furnished the corresponding acids in 62 and 91% yield,
respectively (entries 4 and 5). When p-chlorobenzyl alcohol was
submitted to the optimized conditions complete dechlorination
occurred and benzoic acid was isolated in 76% yield (entry 6).
To prevent the dehalogenation the reaction temperature was
lowered to 150 °C which now allowed p-chlorobenzoic acid to be
isolated in 47% yield (entry 7). p-Bromobenzyl alcohol also
underwent complete dehalogenation in refluxing mesitylene, but
at 150 °C p-bromobenzoic acid could be obtained in 42% yield
(entry 8). The naphthalene substrate 2-naphthylmethanol
afforded the corresponding 2-naphthoic acid in 70% yield (entry
9). 2,4,6-Trimethylbenzyl alcohol, on the other hand, did not
react in the transformation (result not shown) illustrating the
steric effect of the two ortho methyl groups.
[a] Reaction conditions: ZnO (0.4 mmol) and KOH (4 mmol) at 170 °C for 1 h
then add benzylic alcohol (2 mmol) and mesitylene (3 mL) and heat to 164 °C
for 18 h. [b] Isolated yield. [c] Reaction temperature 150 °C.
The transformation could also be applied to aliphatic primary
alcohols although a slower conversion was observed and a
longer reaction time of 36 h was necessary (Table 3). Under
these conditions, heptan-1-ol and decan-1-ol afforded the
corresponding acids in 79 and 82% yield, respectively (entries 1
and 2). 3-Cyclopentyl- and 3-phenylpropan-1-ol gave the 3-
substituted propanoic acids in 74 and 69% yield (entries 3 and
4). Cinnamyl alcohol also furnished 3-phenylpropanoic acid due
to a simultaneous reduction of the olefin (entry 5). Cyclohex-3-
enylmethanol, on the contrary, gave rise to a partial migration of
the olefin and yielded a 2:1 mixture of cyclohex-3-enecarboxylic
acid and cyclohex-1-enecarboxylic acid (entry 6). The bulky
substrate 1-adamantanemethanol could be converted to the acid
as well which was isolated in 67% yield (entry 7). Full or almost
full conversion of the starting material was observed with all the
aliphatic alcohols.
Table 2. Zinc-catalyzed dehydrogenation of benzylic alcohols.[a]
Entry
Substrate
Product
Yield [%][b]
1
85
Table 3. Zinc-catalyzed dehydrogenation of aliphatic alcohols.[a]
2
79
78
62
91
76
47
42
Entry
Substrate
Product
Yield [%][b]
1
79
3
2
3
4
5
82
74
69
75
4
5
6
7[c]
8[c]
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Zinc oxide was submitted to trace metal analysis by
inductively coupled plasma mass spectrometry (ICP-MS) to
exclude other elements known to perform alcohol
dehydrogenation.[23] Fortunately, none of these metals were
observed beyond their detection limits of typically 1 ppm and the
transformation is therefore not believed to be catalyzed by trace
metal residues in zinc oxide.
The catalytically active species is not known and several
experiments were performed in order to gain more information
about the actual catalyst. First, the reaction in Table 1, entry 14
was repeated with 50 L of mercury added from the beginning or
after 2, 4 or 6 h. None of these mercury poisoning experiments
had any significant influence on the yield of benzoic acid and
zinc nanoparticles can therefore be excluded as the actual
catalyst.[17]
6
7
78[c]
67
[a] Reaction conditions: ZnO (0.4 mmol) and KOH (4 mmol) at 170 °C for 1 h
then add aliphatic alcohol (2 mmol) and mesitylene (3 mL) and heat to 164 °C
for 36 h. [b] Isolated yield. [c] Isolated as a 2:1 mixture of cyclohex-3-ene- and
cyclohex-1-enecarboxylic acid.
Next, it was decided to perform a hot filtration test since the
reaction mixture of zinc oxide and potassium hydroxide is
heterogeneous, but the actual catalyst could be a homogeneous
species. Thus, an experiment was performed as in Table 1,
entry 1, but after 35 min with about 15 – 20% alcohol conversion
the mixture was filtered through a nylon syringe filter (0.22 m
pore size) to afford a clear filtrate. This solution was then
refluxed for an additional 18 h to give 59% alcohol conversion
and 45% yield of benzoic acid. This result indicates that a
homogeneous species is formed and is responsible for the
catalytic conversion. Accordingly, it is unlikely that the
transformation takes place on the surface of zinc oxide as has
been proposed in the gas phase dehydrogenation based on
If the amount of potassium hydroxide was lowered, the
aliphatic alcohols produced a mixture of the carboxylic acid and
the corresponding Guerbet alcohol22 (by self-coupling through
an aldol pathway). As an example, heptan-1-ol furnished 51% of
heptanoic acid and 46% of the Guerbet alcohol (2-pentylnonan-
1-ol) with one equiv. of potassium hydroxide while the yields
were 6% and 50%, respectively, with 30% of the base. The
formation of heptanoic acid is due to a faster dehydrogenation of
heptan-1-ol than of the more hindered Guerbet alcohol. However,
it was never possible to optimize the Guerbet coupling to give
more than a moderate yield and this reaction was therefore not
further developed.
kinetic and spectroscopic measurements.[24]
A
control
The evolution of hydrogen gas was measured from the
reaction with zinc oxide in p-cymene (Table 1, entry 7). A total of
61 mL (2.5 mmol) was collected corresponding to approximately
2 equiv. of gas in a reaction with an yield of 73%. The gas was
shown to be H2 which confirms that the transformation takes
place by an acceptorless dehydrogenative pathway. Interestingly,
the measurement showed that the reaction had almost gone to
completion after about 6 h (Figure 1).
experiment was performed where zinc oxide and potassium
hydroxide were refluxed in mesitylene for 35 min (without adding
the alcohol) and then subjected to the same hot filtration. The
alcohol was then added to the clear filtrate and the solution
refluxed for 18 h. This second hot filtration experiment gave no
conversion of the alcohol at all which shows that the alcohol is
involved in the formation of the homogeneous species and this
cannot alone be formed from zinc oxide and potassium
hydroxide.
As a result, the homogeneous species is most likely a zinc
alkoxide which would also explain why the transformation can be
catalyzed by a variety of other zinc(II) species to give similar
results as with zinc oxide. There is to the best of our knowledge
no evidence in the literature for a classical -hydride elimination
pathway with zinc alkoxides to form zinc hydrides.[25] The
enzyme alcohol dehydrogenase reacts by hydride elimination
from a zinc alkoxide, but the hydride is transferred to NAD+.[26]
This, however, does not rule out that a zinc hydride can be
formed at elevated temperature and especially if the carbonyl
compound is removed from the mixture. An experiment was
therefore conducted where 48 mmol of benzyl alcohol was
reacted with 6 mmol of Et2Zn at 0 °C under an inert atmosphere.
The mixture was then slowly heated to 185 °C over 15 h with a
distillation head attached. During this time, 4 mmol of a 5:3
mixture of benzyl alcohol and benzaldehyde distilled off from the
reaction. This experiment shows that a zinc alkoxide can in fact
be decomposed to form the aldehyde (and most likely the
corresponding zinc hydride). A very interesting observation was
Figure 1. Development of hydrogen gas over time. Conditions: BnOH (1
mmol), ZnO (0.2 mmol), KOH (2 mmol), p-cymene (3 mL), 177 °C.
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made when the residue from the distillation was analyzed by
NMR. This showed a 1:1 mixture of benzyl alcohol and benzyl
benzoate showing that a large amount of benzaldehyde was
actually formed in the experiment, but had reacted further to the
ester through a Tishchenko reaction. A recent study showed that
zinc metal catalyzes the Tishchenko reaction where zinc
alkoxides are believed to be the active catalyst formed in situ.[27]
Consequently, we consider the most likely mechanism to
involve a zinc alkoxide and a zinc hydride (Scheme 2). The zinc
alkoxide is first generated from zinc oxide and the alcohol and
then degrades into the aldehyde and the zinc hydride. The latter
deprotonates the alcohol to regenerate the alkoxide in a reaction
that is known to occur readily.[28] The exact pathway for the
conversion of the zinc alkoxide in to the zinc hydride can only be
speculated upon. The classical -hydride elimination is one
possibility if X in Scheme 2 is a vacant coordination site. Another
possibility is an outer-sphere bifunctional pathway if X is an
alcohol. [(HOCH2Ph)Zn–OCH2Ph)] would then be cleaved into
[(PhCH2O…HOCH2Ph)Zn] followed by transfer of the benzylic
hydride to the metal through a six-membered transition state.
This bifunctional pathway has been calculated for hydride
eliminations in NH–metal–alkoxide complexes of osmium,
ruthenium and iron[29] as well as for the Shvo catalyst.[30]
and produced 1 mmol of heptanoic acid together with several
aldol products especially 2-pentylnon-2-en-1-ol. The large
amount of acid after only 2 h cannot be formed from the alcohol
alone, but shows the involvement of a further reaction from the
aldehyde. The intermediate ester, although, could not be
detected under these conditions and is presumably hydrolyzed
rapidly. It is beyond the scope of this study to discuss the
mechanism of the Tishchenko reaction in detail, but it should be
noted that this transformation in some cases is accelerated by
the presence of an alcohol where a bifunctional pathway with the
formation of a metal hydride may be involved.[29a,30]
Conclusions
In summary, zinc oxide has been developed as a catalyst for the
acceptorless dehydrogenation of primary alcohols into carboxylic
acids. The transformation can be applied to both benzylic and
aliphatic alcohols where the former reacts faster than the latter.
The catalytically active species is homogeneous and is believed
to be the corresponding zinc alkoxide. Degradation of the
alkoxide into the aldehyde was confirmed experimentally and
explains the dehydrogenation with the release of hydrogen gas.
The aldehyde can then undergo a disproportionation by either a
Cannizzaro reaction or a Tishchenko reaction to afford a mixture
of the carboxylic acid and the starting alcohol in the presence of
hydroxide.
Experimental Section
General procedure for carboxylic acid synthesis: Zinc oxide (32.60
mg, 0.4 mmol) and potassium hydroxide (224.4 mg, 4 mmol) were placed
in an oven-dried tube, which was placed in a Radley carousel. The flask
was subjected to vacuum and then filled with nitrogen gas (repeated
three times). Vacuum was applied again and the carousel heated to
170 °C for 1 h. Subsequently, the tube was refilled with nitrogen gas.
Anhydrous and degassed mesitylene (3 mL) was added and the mixture
heated to reflux. Alcohol (2 mmol) and tetradecane (0.1 mL as internal
standard) were added by syringe, and the reaction was refluxed with
stirring under a flow of nitrogen for 18 h (benzylic alcohols) or 36 h
(aliphatic alcohols). The mixture was cooled to room temperature and
diethyl ether (5 mL) was added. The white precipitate was filtered off and
washed with diethyl ether (10 mL). The precipitate was dissolved in water
(5 mL) and acidified to pH 1 with 16% aqueous hydrochloric acid. The
aqueous layer was extracted with ethyl acetate (3 × 10 mL). The
combined organic layers were dried over sodium sulfate and
concentrated in vacuo to give the corresponding acid as a pure
compound.
Scheme 2. Proposed mechanism.
In the case of benzaldehyde, the liberated aldehyde can
undergo a Cannizzaro reaction with hydroxide to afford a 1:1
mixture of the carboxylate and the alcohol. We have previously
shown that the Cannizzaro reaction occurs easily under these
conditions.[13d] This was also confirmed when a mixture of
benzaldehyde, potassium hydroxide and zinc oxide was heated
to reflux in mesitylene. Complete conversion of benzaldehyde
was observed after only 30 min and an almost equal mixture of
benzoic acid (55%) and benzyl alcohol (43%) was formed. With
aliphatic alcohols the Tishchenko reaction can account for the
further oxidation to the carboxylic acid level. Several
experiments were performed with heptanal, zinc oxide and
potassium hydroxide, but even at slow addition only aldol
condensation was observed. However, when heptan-1-ol was
also included in the reaction, heptanoic acid was now obtained
Acknowledgements
which is presumably due to
a
zinc alkoxide-mediated
The project was supported by the Villum Fonden (grant 12380).
We thank Cecilie Hauberg Hansen for her assistance in
performing the substrate scope study in Table 1.
Tishchenko reaction followed by ester hydrolysis. In one
experiment 1 mmol of heptanal was added over 1 h to a mixture
of zinc oxide, potassium hydroxide and 1 mmol of heptan-1-ol in
refluxing mesitylene followed by heating for an additional 1 h.
This gave complete conversion of the alcohol and the aldehyde
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10.1002/chem.201804402
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Zinc Oxide-Catalyzed
Dehydrogenation of Primary Alcohols
into Carboxylic Acids
Catalysis at a bargain: Zinc oxide catalyzes the dehydrogenation of primary
alcohols into carboxylic acids with the release of hydrogen gas. It constitutes the
most inexpensive catalyst for the acceptorless alcohol dehydrogenation in solution
where the catalytically active species most likely is a zinc alkoxide.
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